Mitochondria and cell death

Abstract

Mitochondria play a central role in both apoptosis and necrosis through the opening of the mitochondrial permeability transition pore (MPTP). This is thought to be formed through a Ca(2+)-triggered conformational change of the adenine nucleotide translocase (ANT) bound to matrix cyclophilin-D and we have now demonstrated this directly by reconstitution of the pure components. Opening of the MPTP causes swelling and uncoupling of mitochondria which, unrestrained, leads to necrosis. In ischaemia/reperfusion injury of the heart we have shown MPTP opening directly. Recovery of hearts correlates with subsequent closure, and agents that prevent opening or enhance closure protect from injury. Transient MPTP opening may also be involved in apoptosis by initially causing swelling and rupture of the outer membrane to release cytochrome c (cyt c), which then activates the caspase cascade and sets apoptosis in motion. Subsequent MPTP closure allows ATP levels to be maintained, ensuring that cell death remains apoptotic rather than necrotic. Apoptosis in the hippocampus that occurs after a hypoglycaemic or ischaemic insult is triggered by this means. Other apoptotic stimuli such as cytokines or removal of growth factors also involve mitochondrial cyt c release, but here there is controversy over whether the MPTP is involved. In many cases cyt c release is seen without any mitochondrial depolarization, suggesting that the MPTP does not open. Recent data of our own and others have revealed a specific outer-membrane cyt c-release pathway involving porin that does not release other intermembrane proteins such as adenylate kinase. This is opened by pro-apoptotic members of the Bcl-2 family such as BAX and prevented by anti-apoptotic members such as Bcl-X(L). Our own data suggest that this pathway may interact directly with the ANT in the inner membrane at contact sites.

The voltage-dependent anion channel-1 modulates apoptotic cell death

“…VDAC, a major mitochondrial outer membrane transporter, plays an important role in apoptosis by participating in the release of intermembrane space proteins including cytochrome c. 3,4,6,[8][9][10][33][34][35] Investigating the role of VDAC in cellular processes is, however, limited by a lack of tools such Figure 3 RuR inhibits channel activity of native but not E72Q-mutated mVDAC1. Purified native or E72Q-mVDAC1 was reconstituted into a PLB.…”

“…(e) Immunoblot analysis (using anti-VDAC or anti-actin antibodies) of VDAC in cells expressing VDAC1 or E72Q-mVDAC1 with and without exposure to RuR performed 78 h after transfection. Cell extract was obtained as in (d) and 50 mg of protein was subjected to SDS-PAGE Ca 2 þ induces PTP opening and release of cytochrome c. [1][2][3][4]10 Currently, the mitochondrial target of Ca 2 þ has not yet been identified. Several lines of evidence suggest that VDAC possesses Ca 2 þ binding site(s) (for a review see ShoshanBarmatz and Gincel 10 ).…”

“…The release of apoptogenic intermediates such as cytochrome c from the intermembrane space appears to be a central event in the initiation of the cascade that leads to programmed cell death. [1][2][3][4] Mitochondrial Ca 2 þ overload also appears to induce both apoptotic and necrotic cell death. Mitochondria respond to an apoptotic signal by an alteration in the permeability of the mitochondrial membranes, termed permeability transition (PT), and this, in turn, may leads to apoptotic cell death.…”

“…Mitochondria respond to an apoptotic signal by an alteration in the permeability of the mitochondrial membranes, termed permeability transition (PT), and this, in turn, may leads to apoptotic cell death. [1][2][3][4] Two possible models have been proposed for this membrane permeability change. In the first model, an impairment of ATP/ADP antiport leads to hyperpolarization that promotes an osmotic matrix swelling.…”

“…[2][3][4]6 The PT is thought to comprise the adenine nucleotide translocase (ANT), cyclophilin D and the voltagedependent anion channel (VDAC). [2][3][4][6][7][8][9][10] The Ca 2 þ binding component of the permeability transition pore (PTP) has not yet been identified, although Ca 2 þ modulation of the ANT has been suggested. 11 On the other hand, several studies have shown that VDAC is permeable to Ca 2 þ and possesses Ca 2 þ binding site(s), suggesting the involvement of these sites in the regulation of VDAC activity, as well as of PTP opening.…”